This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 4/1/2008 Major depressive disorder (MDD) is a chronic, disabling illness affecting about 17% of the general population. Despite advances in treatment, about two-thirds of patients fail to respond to an initial trial of pharmacotherapy. As MDD continues to pose a significant public health problem, with high rates of morbidity and mortality, well-tolerated new treatments are necessary. Brain-derived neurotrophic factor (BDNF), a polypeptide found naturally in the central nervous system, is responsible for promoting cell growth and survival. Neurodegenerative illnesses such as Huntington's disease (HD), cause a decrease in release of BDNF, and thereby affect neuronal viability. Defective BDNF pathways have also been associated with psychiatric illnesses, such as Alzheimer's dementia and MDD. A multitude of studies have shown low levels of BDNF in subjects with MDD, which have normalized after treatment with an antidepressant. It is presumed that traditional antidepressants such as serotonin reuptake inhibitors increase BDNF via an indirect cascade pathway. Cysteamine is a transglutaminase inhibitor approved for treatment of cystinosis, a lysosomal storage disease. In a preclinical and postmortem study of HD, cysteamine has been shown to increase BNDF in neuronal tissue, and stimulate cell growth. Cysteamine has already been investigated in humans as a potential treatment for HD. Given the ample evidence of decreased levels in major depression, and subsequent increase post-treatment with antidepressants, BDNF may play a key role in developing a novel pathway of treatment for patients who have failed in trials with conventional agents. Therefore, drugs that can demonstrably increase central BDNF, such as cysteamine, may have great use as antidepressant medications. The primary purpose of the study is to assess the acute efficacy of cysteamine, a transglutaminase inhibitor, given in an open-label fashion to patients with recurrent or chronic unipolar major depression without psychotic features. This will be achieved by measuring the mean change in the Montgomery-[unreadable]sberg Depression Rating Scale (MADRS) total score from baseline to the score at the end of 8 weeks of therapy. Hypothesis: Our primary hypothesis is that patients receiving therapy with cysteamine will have decreased symptoms of depression (as evidenced by mean reduction in MADRS score of >25%) at study end point (8 weeks) as compared to baseline. Our first exploratory secondary aim is to explore whether patients with major depression receiving open treatment with cysteamine will manifest improved cognitive function, especially memory. This will be measured by change in neuropsychological test battery scores from baseline to the end of treatment. Our second is to explore whether patients receiving cysteamine openly for eight weeks will demonstrate an increase in serum and cerebrospinal fluid (CSF) concentrations of brain derived neurotrophic factor (BDNF) from pre-treatment to the end of treatment.